The focus of this research is the synaptic nests of the mammalian cochlear nucleus. The unifying hypothesis is that the nests are structured so as to mediate plastic changes in response to acoustic overstimulation and damage to the auditory system. These newly discovered nests consist of aggregations of closely packed synaptic endings which are unusual in not being separated from each other by glial processes. The nests occur throughout the cochlear nucleus and may reach their greatest development in the human. Their fine structure and lack of astrocytic processes having high-affinity glutamate transporters may endow the nests with an unusual potential for producing plastic changes to ongoing stimulation and to damaging levels of noise. A specific hypothesis is that overstimulation produces structural and histochemical changes, including chronic degeneration and new growth of synaptic endings in the nests and the regions associated with them. To see if the balance of excitatory and inhibitory input is thereby disturbed, the analysis will focus on the relative proportions of the different types of synaptic ending in the nests, the transmitter-related molecules associated with them, their origins, and the plastic changes they undergo in response to noise damage. Electron microcopy will be used to characterize the fine structure and quantify the types of synaptic endings in the nests of the chinchilla and mouse cochlear nucleus. The origins of the major inputs for each type of ending will be determined with anterograde-labeling and silver-degeneration methods. Immunocytochemistry and in situ hybridization will be used to identify the transmitter-related molecules associated with each type of ending. These normative data will be used as a basis for determining changes in the relative proportions of ending types in the nests following exposure to noise. These findings will suggest ways of perturbing the degenerative and regenerative changes of these endings, including the insertion of small lesions, cells or latex microspheres for delivery of growth factors, and single gene deletions or overexpression. These changes may account for some of the auditory dysfunction in human nerve deafness caused by noise, including tinnitus and loudness recruitment. The perturbation experiments should lead directly to proposals for new therapies in this disorder.